Labdane process

ABSTRACT

Novel labdanes, intermediates and processes for the preparation thereof, and methods for reducing intraocular pressure utilizing compounds or compositions thereof are disclosed.

This is a division of application Ser. No. 410,834 filed Sept. 21, 1989,which is a continuation of application Ser. No. 106,305 filed Oct. 9,1987 now abandoned, which is a continuation of application Ser. No.921,663 filed Oct. 20, 1986 now abandoned, which is a divisional ofapplication Ser. No. 848,053 filed Apr. 14, 1986 now U.S. Pat. No.4,639,443, which is a continuation-in-part of application Ser. No.707,283 filed Mar. 1, 1985 now abandoned.

The present invention relates to labdanes. More particularly, thepresent invention relates to labdanes of formula 1 ##STR1## wherein

(a) R₁ is hydrogen, a group of the formula R₃ R₄ R₅ Si wherein R₃, R₄and R₅ are each independently loweralkyl, a group of the formula R₂ COwherein R₂ is hydrogen, loweralkyl, or a group of the formula R₂₄ R₂₅NCHR₂₆ wherein R₂₄ is hydrogen, loweralkyl or benzyl, R₂₅ is hydrogen orloweralkyl and R₂₆ is hydrogen, loweralkyl or benzyl; R₂₄ and R₂₅ takentogether with the nitrogen atom to which they are attached form a groupof formula ##STR2## wherein X is O, S or a group of the formula CHR₂₇wherein R₂₇ is hydrogen, loweralkyl or a group of the formula OR₂₈wherein R₂₈ is hydrogen, loweralkyl or a group of the formula COR₂₉wherein R₂₉ is loweralkyl and p is 0 or 1 ;

(b) R₆ and R₇ are each independently hydrogen, a group of the formula R₈CO wherein R₈ is hydrogen, loweralkyl, ##STR3## CH₃ CHOH, HOCH₂ CHOH,(CH₃)₂ COCH₂ OCH₂ CH₂ OCH₃, CH₃ C(CH₃)OH, HOCH₂ C(CH₃)OH, HOCH₂ C(CH₃)₂,CH₃ C(CH₂ OH)₂, C(CH₂ OH)₃, HOC(CH₂ OH)CH₂ CH₃, ##STR4## Wherein R₃₀ isloweralkyl and q is 1, 2 or 3, a group of the formula R₁₀ OCR₃₁ R₃₂(CH₂)_(n) wherein R₁₀ is hydrogen or loweralkyl, R₃₁ is hydrogen orloweralkyl, R₃₂ is hydrogen or loweralkyl and n is 0, 1, 2 or 3, a groupof the formula R₁₁ R₁₂ NCHR₁₃ wherien R₁₁ is hydrogen, loweralkyl, agroup of the formula ##STR5## a group of the formula ##STR6## or a groupof the formula R₁₄ CO wherein R₁₄ is hydrogen or loweralkyl; R₁₂ ishydrogen or loweralkyl; R₁₃ is hydrogen, loweralkyl, benzyl or a groupof the formula CH₂ OH; R₁₁ and R₁₂ taken together with the nitrogen atomto which they are attached form a group of the formula ##STR7## whereinX is O, S or a group of the formula CHR₁₅ wherein R₁₅ is hydrogen,loweralkyl or a group of the formula OR₁₆ wherein R₁₆ is hydrogen,loweralkyl or a group of the formula COR₁₇ wherein R₁₇ is loweralkyl andm is 0 or 1; a group of the formula NR₁₈ wherein R₁₈ is loweralkyl; andR₆ and R₇ taken together form a group of the formula CO or a group ofthe formula SO;

(c) R₉ is hydrogen;

(d) R₁ and R₉ taken together form a group of the formula CO, a group ofthe formula SO or a group of the formula CHNR₁₉ R₂₀ wherein R₁₉ and R₂₀are each independently loweralkyl; and R₁₉ and R₂₀ taken together withthe nitrogen atom to which they are attached form a group of the formula##STR8## wherein X and m are as hereinbeforedescribed; with theprovisos:

(e) that R₆ is not hydrogen or R₈ CO wherein R₈ is hydrogen orloweralkyl when R₇ is hydrogen or R₈ CO wherein R₈ is hydrogen orloweralkyl; R₁ is hydrogen, R₂ CO or R₃ R₄ R₅ Si wherein R₃,R₄ and R₅are as above; and R₉ is hydrogen;

(f) that R₁ is not hydrogen or R₂ CO when R₉ is hydrogen and R₆ and R₇taken together are CO;

(g) that R₁ and R₉ taken together are not CO or SO when R₆ is hydrogenor R₈ CO wherein R₈ is hydrogen or loweralkyl; and R₇ is hydrogen or R₈CO wherein R₈ is hydrogen or loweralkyl; or when R₆ and R₇ takentogether are CO or SO; the optical and geometric isomers thereof, or apharmaceutically acceptable acid addition salt thereof, which are usefulfor reducing intraocular pressure, alone or in combination with inertadjuvants.

Subgeneric to the labdanes of the present invention are compounds offormula 1 wherein:

(a) R₁ and R₉ are hydrogen and R₆ is a group of the formula R₈ COwherein R₈ is a group of the formula R₁₁ R₁₂ NCHR₁₃ wherein R₁₁, R₁₂ andR₁₃ are as hereinbeforedefined;

(b) R₁ and R₉ are hydrogen and R₇ is a group of the formula R₈ COwherein R₈ is a group of the formula R₁₁ R₁₂ NCHR₁₃ wherein R₁₁, R₁₂ andR₁₃ are as hereinbeforedefined;

(c) R₁ and R₉ are hydrogen and R₆ is R₈ CO wherein R₈ is a group of theformula ##STR9## CH₃ CHOH, HOCH₂ CHOH, CH₃ C(CH₃)OH, (CH₃)₂ COCH₂ OCH₂CH₂ OCH₃, ##STR10## wherien R₃₀ is loweralkyl and q is 1, 2 or 3, agroup of the formula R₁₀ OCR₃₁ R₃₂ (CH₂)_(n) wherein R₁₀ is hydrogen orloweralkyl, R₃₁ is hydrogen or loweralkyl, R₃₂ is hydrogen or loweralkyland n is 0, 1, 2 or 3;

(d) R₁ and R₉ are hydrogen and R₇ is a group of the formula R₈ COwherein R₈ is a group of the formula ##STR11## CH₃ CHOH, HOCH₂ CHOH,(CH₃)₂ COCH₂ OCH₂ CH₂ OCH₃, CH₃ C(CH₃)OH, HOCH₂ C(CH₃)OH, HOCH₂ C(CH₃)₂,HOC(CH₂ OH)CH₂ CH₃, ##STR12## wherein R₃₀ is loweralkyl and q is 1, 2 or3, and a group of the formula R₁₀ OCR₃₁ R₃₂ (CH₂)_(n) wherein R₁₀ ishydrogen or loweralkyl, R₃₁ is hydrogen or loweralkyl, R₃₂ is hydrogenor loweralkyl and n is 0, 1, 2 or 3; and

(e) R₁ and R₉ taken together form a group of the formula CHNR₁₉ R₂₀wherein R₁₉ and R₂₀ are as hereinbeforedefined.

The present invention also relates to compounds of the formula 19##STR13## wherein R₄ is hydrogen, loweralkyl or benzyl; R₆ is hydrogenor a group of the formula R₅ CO wherein R₅ is hydrogen or loweralkyl; R₇is hydrogen or a group of the formula R₈ CO wherein R₈ is ashereinbeforedescribed; Hal is chloro or bromo; or the optical andgeometric isomers thereof, which are useful as intermediates for thepreparation of the aminoacyllabdanes of the present invention.

A compound of formula 19 wherein Hal is bromo is prefered.

As used through the specification and appended claims, the term "alkyl"refers to a straight or branched chain hydrocarbon radical containing nounsaturation and having 1 to 8 carbon atoms such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl,2-octyl, and the like; the term "alkanol" refers to a compound formed bya combination of an alkyl group and a hydroxy radical. Examples ofalkanols are methanol, ethanol, 1- and 2-propanol, 1,2-dimethylethanol,hexanol, octanol and the like. The term "alkanoic acid" refers to acompound formed by combination of a carboxyl group with a hydrogen atomor alkyl group. Examples of alkanoic acids are formic acid, acetic acid,propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid,and the like; the term "halogen" refers to a member of the familyconsisting of fluorine, chlorine, bromine or iodine The term "alkanoyl"refers to the radical formed by removal of the hydroxyl function from analkanoic acid. Examples of alkanoyl groups are formyl, acetyl,propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, and the like. Theterm "acyl" encompasses the term "alkanoyl" and refers to the radicalderived from an organic acid by removal of the hydroxyl function.Examples of acyl radicals are tetrahydrofuroyl,2-methyltetrahydrofuroyl, 2,2-dimethyl-1,3-dioxolanoyl,2,3-dihydroxypropionoyl, pyroglutamoyl, N-(2-nitrophenylsulfenyl)prolyl,prolyl, methoxyacetoxy, 1,2:3,4-diisopropylidine-D-galacturonoyl, and3-(dimethylphosphinyl)propionoyl, and the like. The term "lower" asapplied to any of the aforementioned groups refers to a group having acarbon skeleton containing up to and including 6 carbon atoms.

In the formulas presented herein the various substituents areillustrated as joined to the labdane nucleus by one of two notations: asolid line (--) indicating a substituent which is in the β-orientation(i.e., above the plane of the molecule) and a broken line (- - -)indicating a substituent which is in the α-orientation (i.e., below theplane of the molecule). The formulas have all been drawn to show thecompounds in their absolute stereochemical configuration. Inasmuch asthe starting materials having a labdane nucleus are naturally occurringor are derived from naturally occurring materials, they, as well as thefinal products, have a labdane nucleus existing in the single absoluteconfiguration depicted herein. The processes of the present invention,however, are intended to apply as well to the synthesis of labdanes ofthe racemic series.

In addition to the optical centers of the labdane nucleus, thesubstituents thereon may also contain chiral centers contributing to theoptical properties of the compounds of the present invention andproviding a means for the resolution thereof by conventional methods,for example, by the use of optically active acids. A wavy line (˜)connecting a group to a chiral center indicates that the stereochemistryof the center is unknown, i.e., the group may exist in any of thepossible orientations. The present invention comprehends all opticalisomers and reacemic forms of the compounds of the present inventionwhere such compounds have chiral centers in addition to those of thelabdane nucleus.

The novel labdanes of the present invention are synthesized by theprocesses illustrated in Reaction Scheme A, B, and C.

To prepare a basic labdane 3 wherein R₇ is alkanoyl and R₁₉ and R₂₀ areas hereinbeforedescribed, a 1α,9α-dihydroxylabdane 2 wherein R₇ isalkanoyl is condensed with a formamide dialkylacetal of formula 10##STR14## wherein R₂₁ is alkyl and R₁₉ and R₂₀ are ashereinbeforedescribed to provide a basic labdane 3. The condensation ispreferably performed in the absence of an added solvent, excessformamide dialkylacetal serving both as the reactant and solvent. Adipolar aprotic solvent such as dimethylformamide, dimethylacetamide,hexamethylphosphoramide or dimethylsulfoxide may be employed, however,as the reaction medium. The temperature at which the condensation isconducted is not critical A condensation temperature within the range ofabout 25° to about 100° C. is generally employed to assure a reasonablerate of reaction A temperature of about 45° to about 65° C. ispreferred.

To prepare a labdane of formula 4 wherein R₁₉ and R₂₀ are as before andR₆ is alkanoyl, a 7β-alkanoyloxy-6β-hydroxy-labdane 3 is rearranged to a6β-alkanoyloxy-7β-hydroxylabdane 4. The rearrangement is convenientlyperformed in an aqueous alkanol containing an alkali metal hydroxide.Among alkanols there may be mentioned methanol, ethanol, 1- and2-propanol and t-butanol. Methanol is preferred. Among alkali metalhydroxides there may be included lithium, sodium and potassiumhydroxide. Sodium hydroxide is preferred. While the rearrangement ispreferably performed at about ambient temperature, it may be conductedat a reduced temperature within the range of about 0° to about 25° C.,or at an elevated temperature of about 25° to 35° C.

The rearrangement may preferably be effected, for example, by treating 3with lithium 1,1,1,3,3,3-hexamethyldisilazide in an ethereal solventsuch as tetrahydrofuran, dioxane, 1,2-dimethoxyethane orbis-(2-methoxyethyl)ether at a reduced temperature of about 0° C.

To furnish a basic labdane of formula 5 wherein R₁₉ and R₂₀ are asabove, a 6β-alkanoyloxy-7β-hydroxylabdane 4 is hydrolyzed to the 6β,7β-dihydroxylabdane 5. The hydrolysis is carried out in an aqueous alkanolsuch as aqueous methanol, ethanol, 1- or 2-propanol or t-butanol,aqueous methanol being preferred, containing an alkali carbonate such aslithium, sodium or potassium carbonate, potassium carbonate beingprefered, at a hydrolysis temperature within the range of about 10° toabout 75° C., a hydrolysis temperature of about 25° C. being preferred.

A 6β,7β-dihydroxylabdane of formula 5 may also be prepared by hydrolysisof a 7β-alkanoyloxy-6β-hydroxylabdane of formula 3 by means of thehereinbeforedescribed processes for the conversion of 4 to 5.

To introduce a 6β,7β-sulfite or 6β,7β-carbonate function into the basiclabdane nucleus, i.e., to prepare a compound of formula 7 wherein X isSO or CO, respectively, a 6β,7β-dihydroxylabdane of formula 5 is treatedwith a compound of formula 11.

    HalXHal                                                    11

wherein Hal is bromo or chloro, preferably chloro, and X is SO or CO inthe presence of an organic base such as trimethyl- or triethylamine,pyridine, lutidine or collidine at a reduced temperature within therange of about -25° to about 25° C. The preferred organic base ispyridine and the preferred reaction temperature is about 0° C.

To elaborate a basic labdane characterized by the presence ofaminoacyloxy and aminoacetal moieties, a 7β-hydroxylabdane 5 isesterified with an aminoacid of formula 12.

    R.sub.11 R.sub.12 NCHR.sub.13 CO.sub.2 H                   12

wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedescribed. Theesterification is conveniently effected in a halocarbon such asdichloromethane or tirchloromethane in the presence of a carbodiimidesuch as dicyclohexylcarbodiimide and a catalyst such as4-(N,N-dimethylamino)pyridine at a reaction temperature within the rangeof about 0° to about 50° C. Dichloromethane and dicyclohexylcarbodiimideare the preferred halocarbon and carbodiimide, respectively. A reactiontemperature of about 25° C. is also preferred. A hydrohalide of theaminoacid, for example, an aminoacid hydrochloride, may be employed inthe process for the esterification of a 7β-hydroxylabdane.

To construct a basic labdane characterized by an aminoacyloxy functionat the 7β-position and a free hydroxy group at the 1 -position of thelabdane nucleus, i.e., to synthesize a compound of formula 9 whereinR₁₁, R₁₂ and R₁₃ are as hereinbeforedefined, a 7β-alkanoyloxylabdane 2is hydrolyzed under conventional conditions utilizing an alkali metalcarbonate such as sodium carbonate in an aqueous alkanol such asmethanol at a reaction temperature of about 25° C. to the known1α,6β,7β,9α-tetrahydroxy labdane 8 which is esterified with a compoundof the formula 12.

    R.sub.11 R.sub.12 NCHR.sub.13 CO.sub.2 H                   12

wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedefined under reactionconditions substantially similar to those employed for the conversion of5 to 6 described above.

Alternatively, basic labdanes of formula 9 may be prepared by hydrolysisof the aminoacetal moiety of labdanes of formula 6. The hydrolysis maybe accomplished by treating an aminoacetal of formula 6 with an alkanoicacid such as acetic or propanoic acid, preferably acetic acid, in anaqueous alkanol such as methanol, ethanol or 1- or 2-propanol,preferably aqueous methanol, at a temperature within the range of about0° to 50° C., preferably at a temperature of about 25° C.

Basic labdanes of formula 9 are also prepared by desilylation of acompound of formula 15. The removal of the silyl group is achieved by,for example, treating the 1α-silyoxylabdane 5 with aqueous hydrogenfluoride in acetonitrile at a temperature of about 25° C.

To gain entry into the labdane system having a basic moiety at the7β-position and a silyloxy group at the 1α-position, i.e., to providebasic labdanes of formula 15 wherein R₃, R₄, R₅, R₁₁, R₁₂, and R₁₃ areas above, a 7β-alkanoyloxy-1α-hydroxylabdane 2 is silylated to a7β-alkanoyloxy-1α-silyloxylabdane 13 which is hydrolyzed to a7β-hydroxy-1α-silyloxylabdane 14 and converted to a basic labdane 15.

To effect the silylation, one treats a 1α-hydroxylabdane 2 with aN-(trialkylsilyl)-N-alkyltrifluoroacetamide of formula 16

    R.sub.3 R.sub.4 R.sub.5 SiNR.sub.23 COCCF.sub.3            16

wherein R₃, R₄ and R₅ are as above and R₂₃ is alkyl, preferably atrifluoroacetamide wherein R₂₃ is alkyl, most preferablyN-(t-butyldimethylsilyl)-N-methyltrifluoroacetamide, in a dipolaraprotic solvent such as dimethylformamide, dimethylacetamide,hexamethylphosphoramide or dimethylsulfoxide, preferablydimethylformamide, at a temperature within the range of about 0° to 75°C., preferably at a reaction temperature of about 25° C., to afford acompound of formula 13.

The hydrolysis is accomplished by treating a7β-alkanoyloxy-1α-trialkylsilyloxylabdane 13 with an alkali metalcarbonate in an aqueous alkanol. Included among alkali metal carbonatesare lithium, sodium and potassium carbonate. Included among alkanols aremethanol, ethanol, 1- and 2- propanol and t-butanol. Potassium carbonateand methanol are the preferred alkali metal carbonate and alkanol. Whilethe reaction temperature is not narrowly critical, it is preferable toperform the hydrolysis at an elevated temperature within the range ofabout 60° to about 100° C. A hydrolysis temperature of about 80° C. ismost preferred.

The introduction of the basic moiety at the 7β-position of the labdanenucleus, i.e., the conversion of a 7β-hydroxylabdane 14 to a7β-aminoalkylcarbonyloxylabdane 15 is acnieved by processessubstantially similar to those employed for the conversion of 7-hydroxylabdane 5 to 7β-aminoalkylcarbonyloxylabdane 6. For example, onetreats a 7α-hydroxylabdane 14 with an aminoacid 12, free or as thehydrohalide salt, in a halocarbon solvent such as dichloromethane in thepresence of a catalyst such as 4-dimethylaminopyridine and acarbodiimide such as dicyclohexylcarbodiimide at about ambienttemperature (ca. 25° C.) to provide a compound of formula 15.

To synthesize a labdane having a 6β,7β-sulfite or 6β,7β-carbonatefunction and a 1α-hydroxy group, i.e., a compound of formula 18 whereinX is SO or CO, a 1α-silyloxylabdane of formula 14 is converted to a1α-silyloxylabdane -6β,7β-sulfite or -carbonate of formula 17 byprocesses substantially similar to those employed for the conversion ofa compound of formula 5 to a compound of formula 7 followed bydesilylation by the process described above for the transformation of a1α-silyloxylabdane 15 to a 1α-hydroxylabdane 9.

To prepare an aminoacyllabdane 2 wherein R₆ or R₇ is acyl, a1α-hydroxylabdane 2 wherein R₆ or R₇ is acyl is acylated with ahaloalkylcarbonyl halide of the formula 19

    HalCHR.sub.26 COHal                                        19

wherein R₂₆ is as hereinbeforedescribed and Hal is chloro or bromo toprovide a 1α-haloalkanoyloxylabdane 20 which is condensed with an amineof the formula 21

    R.sub.2 R.sub.3 NH                                         21

to afford 22.

The acylation of hydroxylabdane 2 is readily accomplished by treating ahydroxylabdane 2 with a haloalkylcarbonyl halide 19 such asbromoalkylcarbonyl bromide or a chloroalkylcarbonyl chloride, abromoalkylcarbonyl bromide being preferred, in a halocarbon in thepresence of a tertiary amine. Among halocarbons, there may be mentioneddichloromethane, trichloromethane, 1, 1- and 1,2-dichloromethane and1,1- and 1,2-dichloroethene. Dichloromethane is the preferredhalocarbon. Among tertiary amines, there may be mentioned, for example,4-dimethylaminopyridine and N,N-dimethylaniline. N,N-Dimethylaniline isthe preferred amine. While the temperature at which the acylation isperformed is not narrowly critical, it is preferred to conduct thereaction at a temperature within the range of about -0° to about 50° C.It is most preferred to perform the acylation at a temperature withinthe range of about 0° to about 25° C.

The condensation is effected by treating a haloalkanoyloxylabdane 20with a primary or secondary amine 21 in an alkyl alkanoate orhalocarbon, or a mixture thereof. Included among alkyl alkanoates aremethyl acetate, ethyl acetate and ethyl propanoate. Included amonghalocarbons are dichloromethane, trichloromethane, 1,1- and1,2-dichloromethane. Ethyl acetate and dichloromethane are the preferredsolvents. The condensation is preferably performed in the absence ofadded base. An alkali metal bicarbonate such as lithium, sodium orpotassium bicarbonate may, however, be utilized The condensationtemperature is not critical. The converstion proceeds readily at atemperature within the range of about 0° to about 50° C. A reactiontemperature of about 25° C. is preferred.

To introduce a 7β-acyloxy function into the labdane nucleus, i.e., toprepare a compound of formula 25 wherein R₇ is acyl, a 7β-hydroxylabdaneof formula 23 is treated with an organic acid of the formula

    R.sub.8 CO.sub.2 H                                         24

wherein R₈ is as hereinbeforedescribed in a halocarbon such asdichloromethane or trichloromethane in the presence of a carbodiimidesuch as dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and a catalyst such as4-(N,N-dimethylamino)pyridine or 4-(N-pyrrolidyl)pyridine at a reactiontemperature within the range of about 0° to about 50° C. Dichloromethaneis the preferred solvent. A reaction temperature of about 25° C. is alsopreferred.

To prepare a 6β-acyloxylabdane 26 wherein R₆ is acyl, a7β-acyloxylabdane 25 is rearranged to 26 by means of an alkali metalbis(triloweralkylsilyl)amide in an ethereal or hydrocarbon solvent at areduced temperature of about -25° C. to about 25° C., a temperature ofabout 0°C. being preferred. Suitable ethereal solvents includetetrahydrofuran, dioxane, 1,2-dimethoxyethane andbis(2-methoxyethyl)ether. Tetrahydrofurane is preferred. Suitable alkalimetal bis(triloweralkylsilyl)amides include lithium, sodium andpotassium bis(trimethyl-, triethyl- and tripropylsilyl)amide. Lithiumbis(trimethylsilyl)amide is preferred.

To prepare an acyloxylabdane of formula 25 or 26 characterized by thepresence of a dihydroxyalkanoyl group at the 7β- or 6β-position,respectively, a dioxolanoyloxylabdane of formula 25 or 26 wherein R₇ orR₈ is dioxolanoyl is cleaved to afford the desired dihydroxyalkanoylderivative. The cleavage is accomplished by contacting thedioxolanoyllabdane 25 or 26 with an alkanoic acid or an aqueous alkanoicacid is an alkanol. Among alkanoic and aqueous alkanoic acids, there maybe mentioned acetic acid, aqueous acetic acid, proprionic acid, aqueouspropionic acid and the like. Among alkanols there may be mentionedmethanol, ethanol, 1- and 2-propanol, t-butanol and the like. Aqueousacetic acid is preferred. Acetic acid (80%) is most preferred. Methanolis also preferred. While the cleavage proceeds readily at a reactiontemperature within the range of about 0° to aobut 65° C., a reactiontemperature within the range of about 25° to 50° C. is preferred.

The labdane starting materials for the processes of the presentinvention, i.e., labdanes of formula 3 wherein R₇ is hydrogen or a groupof the formula R₈ CO wherein R₈ is as hereinbeforedescribed, aredescribed in U.S. Pat. No. 4,134,986, issued Jan. 16, 1979 to B. S.Bajwa, et al., or may be prepared from compounds disclosed therein byconventional processes.

The labdanes of the present invention are useful in the treatment ofelevated intraocular pressure by virtue of their ability to reduceintraocular pressure as determined by the method described by J.Caprioli, et al., Invest. Ophthalmol. Vis. Sci., 25, 268 (1984). Theresults of the determination expressed as percent decrease of outflowpressure is presented in the Table.

                  TABLE                                                           ______________________________________                                                                    DECREASE IN                                                      CONCENTRA-   OUTFLOW                                           COMPOUND       TION (%)     PRESSURE (%)                                      ______________________________________                                        7β-(N,N-diethylamino-                                                                   2            36                                                acetoxy)-8,13-epoxy-                                                          1α,6β,9α-trihydroxylabd-                                     14-en-11-one 1,9-                                                             dimethylformamide acetal                                                      7β-(N-acetylamino-                                                                      2            59                                                acetoxy)-8,13-epoxy-                                                          1α,6β,9α,trihydroxy-                                         labd-14-en-11-one                                                             7β-[2-[(N-t-butoxy-                                                                     1            43                                                carbonyl)amino]pro-                                                           panoyloxy]-8,13-                                                              epoxy-1α,6β,9α-                                              trihydroxylabd-14-en-                                                         11-one                                                                        7β-(N,N-diethylamino-                                                                   2            27                                                acetoxy)-8,13-epoxy-                                                          1α,6β,9α-trihydroxy-                                         labd-14-en-11-one                                                             7β-(N,N-dimethyl-                                                                       2            30                                                aminoacetoxy)-8,13-                                                           1α,6β,9α-trihydroxy-                                         labd-14-en-11-one                                                             8,13-epoxy-1α,6β,9α-                                                        2            51                                                trihydroxy-7β-(2-                                                        tetrahydrofuranoyl-                                                           oxy)labd-14-en-11-one                                                         7β-acetoxy-8,13-epoxy-                                                                    1.0        51                                                1α,6β,9α-trihydroxy-                                                          0.1        23                                                labd-14-en-11-one                                                             ______________________________________                                    

Intraocular pressure reduction is achieved when the present labdanes areadministered to a subject requiring such treatment as an effectivetopical dose of a 0.01 to 3.0% solution or suspension. A particularlyeffective amount is about 3 drops of a 1% preparation per day. It is tobe understood, however, that for any particular subject, specific dosageregimens should be adjusting according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the aforesaid compound. It is to be further understoodthat the dosages set forth herein are exemplary only and that they donot, to any extent, limit the scope or practice of the invention.

Compounds of the present invention are also useful for the treatment ofhypertension, congestive heart failure, bronchial asthma and psoriasis.

Compounds of the present invention include:

(1)1α-acetoxy-7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-6β,9.alpha.-dihydroxylabd-14-en-11-one.

(2) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-6β-hydroxylabd-14-en-11-one1α,9α-sulfite.

(3)7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one1,9-pyrrolidineformamide acetal.

(4) 6β-[N-(t-butoxycarbonyl)aminoacetoxy]-8,13-epoxy-1α,7β,9α-trihydroxylabd-14-en-11-one.

(5) 8,13-epoxy-7β-formyloxy-b 1α,6β,9α-trihydroxylabd-14-en-11-one 1,9dimethylformamide acetal.

(6) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α-formloxy6β,9α-dihydroxylabd-14-en-11-one.

(7) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-6β-hydroxylabd-14-en-11-one1α,9α-carbonate.

(8)7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one1,9 piperidineformamide acetal.

(9)7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one1,9 morpholineformamide acetal.

(10)7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one1,9 thiomopholineformamide acetal.

(11) 8,13-epoxy-1α,9α-dihydroxylabd-14-en-one 1,9-dimethylformamideacetal 6β,7β-carbonate.

(12) 7β-aminoacetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.

(13)7β-(1-piperidinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.

(14)7β-(1-pyrrolidinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.

(15) 7β-(4-morpholinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.

(16)7-β(4-thiomopholinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.

(17)8,13-epoxy-1α,6β,9α-trihydroxy-7β-(2-aminopropionyloxy)labd-14-en-11-one.

(18) 8,13-epoxy- 1α,6β,9α-trihydroxy-7β-(2-amino-3-phenylpropionyloxy)labd-14-en-11-one.

(19)7β-(2,3-dihydroxy-2-methylpropionyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.

(20)8,13-epoxy-7β-(3-hydroxy-2,2-dimethylpropionyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.

(21)8,13-epoxy-7β-(2-hydroxymethyl-2-hydroxybutyroyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.

(22)8,13-epoxy-7β-(2,2-dihydroxymethylpropionyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one.

(23)8,13-epoxy-7β-(2,2-dihydroxymethyl-3-hydroxypropionyloxy)-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.

Effective amounts of the compounds of the present invention may beadministered to a subject by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, in some cases intravenously in the form ofsterile solutions, or suspensions, and topically in the form ofsolutions, suspension or ointments, and by aerosol spray. The labdanesof the present invention, while effective themselves, may be formulatedand administered in the form of their pharmaceutically acceptableaddition salts for purposes of increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid and thelike, and salts of tribasic carboxylic acids such as, for example,citric acid and the like.

Effective quantities of the compounds of the invention may beadministered orally, for example, with an inert diluent or with anedible carrier They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theaforesaid compounds may be incorporated with excipients and used in theform of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gums and the like. These preparations should contain atleast 0.5% of active compound, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of active compound in such composition issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that anoral dosage unit form contains between 0.1-30 milligrams of the activecompound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragancanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, corn starch and the like; alubricant such as magnesium stearate; a glidant such as colloidalsilicon dioxide; and a sweetening agent such as sucrose or saccharin ora flavoring agent such as peppermint, methyl salicylate, or orangeflavoring may be added. When the dosage unit form is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral or topical therapeutic administeration,the active compounds of the invention may be incorporated into asolution, suspension, ointment or cream. These preparations shouldcontain at least 0.01% of active compound, but may be varied between 0.5and about 5% of the weight thereof. The amount of active compounds insuch compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10 milligrams of active compound.

The solutions or suspensions for topical or parenteral administrationmay also include the following components: a sterile diluent such aswater for injection, saline solution, fixed oils, polyethylene glycols,glycerine, proplyene glycol or other synthetic solvents; antibacterialagents such as benzyl alcohol or methyl parabens; antioxidants such asascorbic acid or sodium bisulfite; chelating agents such asethylenediaminetetraacetic acid; buffers such as acetates, citrates orphosphates and agents for the adjustment of tonicity such as sodiumchloride or dextrose. The parenteral preparation can be enclosed inampules or disposable syringes; the topical preparation may be enclosedin multiple dose vials or dropping bottles, made of glass or plastic.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given indegrees Centigrade.

EXAMPLE 17β-Acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

7β-Acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 100 mg) wasdissolved in 1 ml of dimethylformamide dimethyl-acetal. The mixture wasstirred 1 hr at room temperature and overnight at 55° under nitrogen.The mixture was dissolved in ether, washed with water, dried overanhydrous sodium sulfate, filtered and concentrated to an oil. The oilwas dissolved in a minimum volume of dichloromethane and chromatographedusing 10 g of silica gel (230-400 mesh). Eluent: 8×3 ml ofdichloromethane, 8×3 ml of 3% methanol/dichloromethane and 8×3 ml of 5%methanol/dichloromethane. Evaporation of the solvent from appropriatefractions followed by drying at 60° (1 mm) provided 90 mg (79 1%) ofproduct as an oil.

ANALYSIS: Calculated for C₂₅ H₃₉ NO₇ :64.49% C, 8.44% H, 3.01% N, Found:64.69% C, 8.25% H, 3.09% N.

EXAMPLE 26β-Acetoxy-8,13-epoxy-1α,7β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 200 mg of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 2 ml ofdimethylformamide dimethylacetal was stirred at 35° overnight, undernitrogen, and allowed to cool to room temperature. To the mixture wasadded 10 ml of an 20% aqueous methanolic solution of sodium hydroxide.The mixture was stirred overnight at room temperature. The mixture wasdiluted with ethyl acetate, washed twice with water, saturated sodiumchloride solution and dried over anhydrous sodium sulfate. Filtrationfollowed by evaportion of solvent provided an oil. The material wasflash chromatographed using 20 g of silica gel (230-400 mesh) (eluent:50×15 ml of 30/70 ethyl acetate/hexane). Evaporation of the appropriatefractions followed by drying at 80° (1 mm) provided 81 mg (35.6%) ofproduct, mp 173°-175°.

ANALYSIS: Calculated for C₂₅ H₃₉ NO₇ : 64.49% ,C 8.44% H, 3.01% N,Found: 64.59% C, 8.56% H, 2.86% N.

EXAMPLE 38,13-Epoxy-1α,6β,7β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 225 mg of7β-acetoxy-8.13-epoxy-1α,6β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal was stirred at room temperature under nitrogen for 5 hrs in 5 mlof saturated potassium carbonate solution in 20% aqueous methanol. Thesolution was diluted with water and extracted twice with ether. Theether extracts were washed twice with water and dried over anhydroussodium sulfate. Filtration followed by evaporation of the solventprovided an oil, which crystallized on standing. The crystals were driedat 113° (1 mm) to yield 192 mg (88.5%) of product, mp 136°-144°.

ANALYSIS: Calculated for C₂₃ H₃₇ NO₆ : 65.22% C, 8.81% H, 3.31% N,Found: 65.18% C, 8.76% H, 3.25% N.

EXAMPLE 48,13-Epoxy-1α,9α-dihydroxylabd-14-en-11-one-1α,9α-dimethyformamideacetal -6β,7β-sulfite

To a stirred solution of 200 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1α,9α-dimethylformamideacetal in 2 ml of dry pyridine was added slowly, dropwise, a solution of0.2 ml of thionyl chloride in 4 ml of dry pyridine. The mixture wasstirred 15 min at 0°, poured into water, and extracted twice with ether.The extracts were washed twice with water, dried over anhydrous sodiumsulfate and filtered. Concentration provided an oil. The material wasdissolved in a minimum volume of 25% ethyl acetate/hexane and purifiedby flask chromatography on 25 g of silica gel (230-400 mesh; eluent:20×15 ml of 25% ethyl acetate/hexane). Concentration of the appropriatefractions followed by drying at 40° (1 mm) provided 0.148 g (66.7%) ofproduct, mp 157°-162°.

ANALYSIS: Calculated for C₂₃ H₃₅ NO₇ S: 58 82% C, 7.51% H, 2.98% N,Found: 58.72% C, 7.51% H, 2.56% N.

EXAMPLE 57β-[N-(t-Butoxycarbonyl)aminoacetoxy]-8,13-epoxy-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

To a mixture of 100 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one, 34.1 mg of4-dimethylaminopyridine and 47.6 mg of N-t-butoxycarbonylglycinedissolved in 5 ml of dichloromethane was added a solution of 61.6 mg ofdicyclohexylcarbodiimide dissolved in 2 ml of dichloromethane. Themixture was stirred under nitrogen for 4 hr. The mixture was filteredand the filtrate was evaporated to dryness. The residue was purified byflash chromatography on silica gel in hexane:ethyl acetate (3:1). Theappropriate fractions were combined and evaporated to dryness undervacuum. The residue was crystallized from hexane, filtered and driedyielding 107.3 mg (75.2%) of product, mp 94°-100°.

ANALYSIS: Calculated for C₂₇ H₄₃ NO₉ : 61.68% C, 8.26% H, 2.66% N,Found: 62.12% C, 8.58% H, 2.57% N.

EXAMPLE 67β-(N,N-Diethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1α,9α-dimethylformamideacetal

To a mixture of 150 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one dimethylformamideacetal, 59.4 mg of diethylglycine hydrochloride, 44.6 mg of4-(N,N-dimethylamino)pyridine in 6 ml of dichloromethane was added 80.5mg of dicyclohexylcarbodiimide dissolved in 3 ml of dichloromethane. Themixture was stirred under nitrogen at ambient temperature overnight. Themixture was filtered and evaporated to dryness under vacuum. The residuewas flash chromatographed in hexane:ethyl acetate (1:1). The appropriatefractions were combined and evaporated to dryness to yield 138.3 mg(72.8%) of product, mp 129°-133°.

ANALYSIS: Calculated for C₂₉ H₄₈ N₂ O₇ : 64.89% C, 9.03% H, 5.22% N,Found: 65.17% C, 8.87% H, 5.46% N.

EXAMPLE 77β-Acetoxy-1α-(t-butyldimethylsilyloxy)-6β,9α-dihydroxy-8,13-epoxylabd-14-en-11-one

To a solution of 1.00 g of7β-aceotxy-8,13,epoxy-1α,6β,9α-tribydroxylabd-14-en-11-one in 5 ml ofdimethylformamide was added, dropwise, 610 ul ofN-(t-butyldimethylsilyl)-N-methyltrifluoroacetamide, and the reactionmixture was stirred for 1 hr. The mixture was allowed to stand at roomtemperature overnight, and was then diluted with 5 ml of one-halfsaturated brine and extracted with diethyl ether. The combined extractswere dried over anhydrous sodium sulfate, filtered and the filtrateswere evaporated. The residue was flash chromatographed on a silica gelcolumn using ethyl acetate-hexane (1:3) as the eluent. Evaporation ofthe appropriate fractions gave 1.24 g (97.2%) of product.

EXAMPLE 81α-(t-Butyldimethylsilyloxy)-8,13-epoxy-6β,7β,9α-trihydroxylabd-14-en-11-one

A solution of 1.24 g of7β-acetoxy-1α-(t-butyldimethylsilyloxy)-8,13-epoxy-6β,9.alpha.-dihydroxylabd-14-en-11-one,4 ml of saturated potassium carbonate solution and 16 ml of methanol washeated at 80° for 1 hr. The reaction mixture was cooled, diluted withsaturated sodium chloride solution, and extracted with ether. Thecombined ether extracts were dried over anhydrous potassium carbonate,filtered, and the filtrate was evaporated. The residue was flashchromatographed on silica gel column using ethyl acetate-hexane (1:3) asthe eluent. Evaporation of the appropriate fractions provided 646 mg(56.5%) of product.

EXAMPLE 97β-(N,N-Dimethylaminocetoxy)-8,13-epoxy-6β,9α-dihydroxy-1.alpha.-(t-butyldimethylsilyloxy)labd-14-en-11-one hydrochloride

8,13-Epoxy-6β,7β,9α-trihydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one(100 mg) was dissolved in 4 ml of dichloromethane with 29.0 mg ofdimethylglycine hydrochloride and 26 0 mg of 4-dimethylaminopyridine. Tothe above mixture was added 48 mg of N,N-dicyclohexylcarbodiimidedissolved in 1 ml of dichloromethane. The mixture was stirred at ambienttemperature for 18 hr. The mixture was filtered through a cotton plugand the filtrate was evaporated to dryness. The residue was suspended inether, filtered and evaporated to dryness. The residue was flashchromatographed on silica gel in hexane:ethyl acetate methanol(10:10:1). The appropriate fractions were combined and evaporated todryness to provide 87.8 mg (74.7%) of product. The product was dissolvedin ether and the hydrochloride precipitated, mp 227°-228°.

ANALYSIS: Calculated for C₃₀ H₅₄ ClNO₇ Si: 59.61% C, 9.02% H, 2.32% N,Found: 60.06% C, 9.22% H, 2.19% N.

EXAMPLE 107β-(N,N-Diethylaminoacetoxy)-8,13-epoxy-6β,9α-dihydroxy-1.alpha.-(t-butyldimethylsilyloxy)labd-14-en-11-onehydrochloride

8,13-Epoxy-6β,7β,9α-trihydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one(50 mg) was combined with 17.4 mg of N,N-diethylglycine hydrochlorideand 13.1 mg of 4-(N,N-dimethyl amino)pyridine in 2 ml of drydichloromethane. Dicylohexylcarbodiimide (24 mg) dissolved in 1 ml ofdichloromethane was added to the above mixture in a sealed tube. Themixture was allowed to stand at ambient temperature overnight. Thedicyclohexylurea was filtered off. After the filtrate was evaporated todryness, the residue was suspended in ethyl acetate and filtered. Thefiltrate was flash chromatographed on silica gel in hexane:ethyl acetate(3:1). The appropriate fractions were combined and evaporated to drynessunder vacuum. The residue was dissolved in ether, from which the productas the hydrochloride was precipitated, and yielded 32.7 mg of product,mp 200°-210°.

ANALYSIS: Calculated for C₃₂ H₅₈ ClNO₇ Si: 60.77% C, 9.26% H, 2.21% N,Found: 60.88% C, 9.68% H, 2.33% N.

EXAMPLE 117β-(N,N-Dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride

7β-(N,N-Dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-onedimethylformamide acetal (103.1 mg) was dissolved in a mixture of 1.4 mlof methanol and 1.4 ml of 80% acetic acid. The mixture was stirred atambient temperature for 3 days after which it was evaporated to dryness.The residue was dissolved in ether and extracted several times with 5%sodium bicarbonate solution. The organic phase was dried over anhydroussodium sulfate, filtered and evaporated to dryness. The residue wasflash chromatographed on silica gel packed in hexane:ethylacetate:methanol (10:10:1). The appropriate fractions evaporated todryness. The residue was dissolved in ether and treated with etherealhydrogen chloride to afford 28 mg (30.5%) of product, mp 255°-260°(dec).

ANALYSIS: Calculated for C₂₄ H₄₀ ClNO₇ : 58.81% C, 8.24% H, 2.86% N,Found: 58.77% C, 8.19% H, 2.73% N.

EXAMPLE 127β-(N,N-Diethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride

7β-(N,N-diethylaminoacetoxy)-8,13-epoxy-1α,6β,9β-trihydroxylabd-14-en-11-one 1,9-dimethylformamide acetal (84.1 mg)was dissolved in 2 ml of a mixture of methanol:acetic acid:water(10:8:2) and allowed to stand overnight under nitrogen at ambienttemperature. The mixture was basified with saturated aqueous sodiumbicarbonate solution. The product was extracted into dichloromethane,dried over anhydrous sodium sulfate, filtered and evaporated. Theresidue was dissolved in ether and treated with ethereal hydrogenchloride. The ether suspension was evaporated and the residue wasresuspended in ether. The solid was filtered and dried under vacuum at80° for 1 hr to yield 42.2 mg (52.0%) of product, mp 149°-156° (dec).

ANALYSIS: Calculated for C₂₆ H₄₃ ClNO₇ : 60.26% C, 8.58% H, 2.70% N,Found: 59.66% C, 8.52% H, 3.11% N.

EXAMPLE 137β-(Methoxyacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (100 mg) wasdissolved in 5 ml of dichloromethane together with 34.2 mg of4-dimethylaminopyridine and 24.5 mg of methoxyacetic acid. To the abovesolution was added 61.7 mg of dicyclohexylcarbodiimide dissolved in 2 mlof dichloromethane, and the mixture was stirred overnight under anatmosphere of nitrogen. The mixture was filtered, evaporated to drynessand loaded onto a flash silica gel column packed indichloromethane:methanol (10:0.2). The appropriate fractions werecombined and evaporated to dryness. Trituration of the residue withhexane provided 49.5 mg (41.4%) of product, mp 164°-170°.

ANALYSIS: Caculated for C₂₃ H₃₆ O₈ : 70% C, 8 25% H, Found: 62.51% C,8.22% H.

EXAMPLE 147β-[2-(N-t-Butoxycarbonyl)aminopropanolyoxy]-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (100 mg) wasstirred with 34.2 mg of 4-dimethylaminopyridine and 51.4 mg ofN-t-butoxycarbonyl-L-alanine in 5 ml of dichloromethane.Dicyclohexylcarbodiimide (61.7 mg) dissolved in 2 ml of dichloromethanewas added to the mixture and was allowed to stand overnight undernitrogen at ambient temperature. The mixture was diluted with ether,filtered and evaporated to dryness. The residue was flashchromatographed on silica gel packed in hexane:ethyl acetate (3:1). Theappropriate fractions were combined and evaporated to dryness.Trituration of the residue with hexane provided 74.1 mg (50.6%) ofproduct, mp 117°-122° (dec).

ANALYSIS: Calculated for C₂₈ H₄₅ NO₉ : 62.31% C, 8.42% H, 2.59% N,Found: 62.20% C, 8.39% H, 2.99% N.

EXAMPLE 157β-(N-Acetylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (100 mg) wasstirred with 34.2 mg of 4-dimethylaminopyridine and 31.8 mg ofN-acetylglycine in 5 ml of dichloromethane. Dicyclohexylcarbodiimide(61.7 mg) dissolved in 2 ml of dichloromethane was added to the solutionand the resultant mixture was stirred under nitrogen at ambienttemperature overnight. The mixture was filtered and evaporated todryness. The residue was flash chromatographed on silica gel packed inhexane:ethyl acetate (1:1). The appropriate fractions were combined andevaporated to dryness. The residue was triturated with cyclohexaneaffording 26.6 mg (21.0%) of product, mp 106°-110°.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₈ : 61.64% C, 7.99% H,. 2.99% N,Found: 62.01% C, 8.27% H, 2.60% N.

EXAMPLE 167β-(4-Morpholinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride hydrate

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (100 mg) wasdissolved in 5 ml of dichloromethane and stirred with 34.2 mg of4-N,N-dimethylaminopyridine and 49.3 mg of (4-morpholino)acetic acidhydrochloride. Dicyclohexyl carbodiimide (61.7 mg) in 2 ml ofdichloromethane was added to the mixture and was stirred under nitrogenovernight at ambient temperature. The mixture was diluted with ether andfiltered. The filtrate was evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (1:1) and elutedwith hexane:ethyl acetate:methanol (10:10:1). The appropriate fractionswere combined and evaporated. The residue was dissolved in ether andtreated with ethereal hydrogen chloride to yield 55.5 mg (38.4%) ofproduct, mp 165°-175° (dec).

ANALYSIS: Calculated for C₂₆ H₄₄ ClNO₉ : 56.76% C, 8.08% H, 2.54% N,Found: 57.01% C, 7.69% H, 2.77% N.

EXAMPLE 177β-[N-(2-Nitrophenylsulfenyl)aminoacetoxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-1,60 ,6β,7β,9α-trihydroxylabd-14-en-11-one (325 mg), 361.7 mgof N-(2-nitrophenylsulfenyl)glycine dicyclohexylammonium salt and 140 mgof 4-N,N-dimethyl.aminopyridine hydrochloride were suspended in 25 ml ofdichloromethane. After dissolution occurred, a solution of 273.3 mg ofdicyclohexycarbodiimide in 5 ml of dichloromethane was added. Themixture was allowed to stand at ambient temperature overnight. Themixture was filtered and the filtrate was evaporated to dryness. Theresidue was flash chromatographed on silica gel indichloromethane:methanol (10:0.2). The appropriate fractions werecombined and evaporated to dryness The residue was crystallized fromhexane:ether yielding, in two crops, 153.5 mg (30.1%) of product, mp104° (dec).

ANALYSIS: Calculated for C₂₈ H₃₈ N₂ O₉ S: 58.11% C, 6.62% H, 4.84% N,Found: 57.63% C, 6.61% H, 5.41% N.

EXAMPLE 188,13-Epoxy-9α-hydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one6β,7β-sulfite

8,13-Epoxy-6β,7β,9α-trihydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one(200 mg) was dissolved in 2.0 ml of pyridine together with 200 ml ofthionyl chloride at 5°. After 0.5 hr, the mixture was poured into waterand extracted with ethyl acetate. The organic extracts were combined,dried over anhydrous sodium sulfate filtered and evaporated to drynessunder vacuum. The residue was flash chromatographed (silica gel,hexane:ethyl acetate (3:1)). The appropriate fractions were combined andevaporated to dryness to give 122.2 mg of product, mp 107°-109°.

ANALYSIS: Calculated for C₂₆ H₄₄ O₇ SSi: 59.05% C, 8.40% H, Found:58.74% C, 8.24% H.

EXAMPLE 19

8,13-Epoxy-1α,9α-dihydroxylabd-14-en-11-one 6β,7β-sulfite

8,13-Epoxy-9α-hydroxy-1α-(t-butyldimethylsilyloxy)-labd14-en-11-one6β,7β-sulfite (487.5 mg) was dissolved in 25 ml of acetonitrile and 40%aqueous hydrofluoric acid (95:5) and stirred at ambient temperature forsix hrs. The mixture was basified with saturated aqueous sodiumbicarbonate solution and the layers were separated. The aqueous phasewas extracted with ethyl acetate which was then combined with theorganic phase. The combined organic phases were dried over anhydroussodium sulfate, filtered and evaporated to dryness. The residue wasflash chromatographed on silica gel in hexane:ethyl acetate (3:1). Theappropriate fractions were combined and evaporated to dryness to provide208.7 mg (54.6%) of product, mp 186°-193° (dec).

ANALYSIS: Calculated for C₂₀ H₃₀ O₇ S: 57.95% C, 7.31% H, Found: 58 27%C, 7.21% H.

EXAMPLE 208,13-Epoxy-1α,6β,9α-trihydroxy-7β-[2-(2-nitrophenylsulfenylamino)propionyloxy]labd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one was dissolved in 50ml of dry dichloromethane along with 863 mg of2-(2-nitrophenylsulfenylamino)propionic acid, dicyclohexylammonium salt,323 mg of 4-dimethylaminopyridine hydrochloride and 547 mg ofdicyclohexylcarbodiimide. The mixture was stirred at ambient temperatureunder nitrogen overnight, after which it was diluted with ether andfiltered. The filtrate was evaporated and the residue was dissolved indichloromethane and flash chromatographed on silica gel packed withdichloromethane:methanol (10:0.2). The appropriate fractions werecombined and evaporated. The residue was crystallized from hexane:etherto give 627.6 mg (53%) of product, mp 209°-216°.

ANALYSIS: Calculated for C₂₉ H₄₁ N₂ O₉ S: 58 76% C, 6.82% H, 4 72% N,Found: 58 60% C, 7.06% H, 4 74% N.

EXAMPLE 218,13-Epoxy-1α,6β,9α-trihydroxy-7β-(2-tetrahydrofuranoyloxy)-labd-14-en-11-one

8,13-Epoxy-1,α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (500 mg) wasdissolved in 50 ml of dry dichloromethane along with 157.6 mg of2-tetrahydrofuroic acid, 174 mg of 4-dimethylaminopyridine and 420 mg ofdicyclohexylcarbodiimide. The mixture was stirred at ambient temperatureunder nitrogen overnight. The mixture was diluted with an equal volumeof ether and was filtered. The filtrate was evaporated and the residuewas flash chromatographed on silica gel in dichloromethane:methanol(10:0.2). The appropriate fractions were combined, evaporated, and theresidue was crystallized from cyclohexane to give 180.5 mg (28.4%) ofproduct, mp 162°-165°.

ANALYSIS: Calculated for C₂₅ H₃₈ O₈ : 64.34% C, 8.23% H, Found: 64.25%C, 8.14% H.

EXAMPLE 22 7β-(1-Piperidinoacetosy)-8,13-epoxy-1α,6β,9α-trihydroxy and14-en-11-one-1,9-dimethylformamide acetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (750 mg) was dissolved in 50 ml of dichloromethane with 318.3 mgof 2-(1-piperidino)acetic acid hydrochloride, 228 mg of4-dimethylaminopyridine and 402 mg of dicyclohexylcarbodiimide. Themixture was stirred for 36 hrs at ambient temperature under nitrogen,diluted with an equal volume of ether and filtered. The filtrate wasevaporated. The residue was flash chromatographed on silica gel inhexane:ethyl acetate (1:1), after which the appropriate fractions werecombined and evaporated. The residue was crystallized from hexane togive 286.5 mg (29.6%) of product, mp 150°-155° (dec)

ANALYSIS: Calculated for C₃₀ H₄₈ N₂ O₇ : 65.65% C, 8.83% H, 5.10% N,Found: 65.68% C, 8.91% H, 5.22% N.

EXAMPLE 237β-(N,N-Dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one1,9-dimethylformamide acetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (750 mg) was dissolved in 50 ml of dichloromethane and stirred atambient temperature overnight, under nitrogen, along withN,N-dimethylglycine hydrochloride (247.5 mg), 4-dimethylaminopyridine(227.5 mg) and dicyclohexylcarbodiimide (402.4 mg). The mixture wasdiluted with an equal volume of ether, filtered and evaporated. Theresidue was flash chromatographed on silica gel in hexane:ethylacetate:methanol (10:2:1). The appropriate fractions were combined andevaporated. The resultant oil was dried under vacuum at 20° to give 800mg (89.0%) of product, mp 55°-60°.

ANALYSIS Calculated for C₂₇ H₄₄ N₂ O₇ : 63.73% C, 8.74% H, 5.50% N,Found: 63.56% C, 8.86% H, 5.33% N.

EXAMPLE 247β-(1-Piperidinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride hemietherate

7α-(1-Piperidinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (259.5 mg) was dissolved in 5 ml of methanol and 5 ml of 80%acetic acid. The mixture was stirred under nitrogen at ambienttemperature overnight, evaporated, diluted with water, neutralized withsodium bicarbonate solution, and extracted with ether. The etherextracts were combined, dried over anhydrous sodium sulfate, filteredand evaporated. The residue was dissolved in anhydrous ether, from whichthe hydrochloride salt was precipitated by addition of etheral hydrogenchloride. The precipitate was filtered, washed with anhydrous ether anddried under vacuum at 110° for 1 hr to afford 168.2 mg (62.6%) ofproduct, mp 190°-194°.

ANALYSIS: Calculated for C₂₉ H₄₉ ClNO₇.5 : 61.40% C, 8.72% H, 2.47% N,Found: 61.11% C, 8.88% H, 2.59% N.

EXAMPLE 251α-(N-t-Butylaminoacetoxy)-6β,9α-dihydroxy-8,13-epoxy-7.beta.-(2-tetrahydrofuroyloxy)-labd-14-en-11-onehydrochloride hydrate

8,13-Epoxy-1α,6β,9α-trihydroxy-7β-(2-tetrahydrofuroyloxy)labd-14-en-11-one(200 mg) was dissolved in dry dichloromethane (2 ml) along withdimethylaniline (58.7 μl) with cooling to 5°. A solution of bromoacetylbromide (49.1 μl) in dry dichloromethane (2 ml) was added dropwise over0.5 hr to the solution. After 1 hr at 5°, the mixture was allowed towarm to ambient temperature and poured onto a mixture of ice andsaturated aqueous sodium bicarbonate solution. The solution wasextracted with ethyl acetate and the organic extract was dried overanhydrous sodium sulfate, filtered and evaporated. The residue wasdissolved in dry dichloromethane (1 ml) and stirred under nitrogen. Asolution of t-butylamine (91.2 μl) in ethyl acetate (2 ml) was added.The mixture was stirred at ambient temperature overnight, diluted withdichloromethane (10 ml) and washed with water followed by saturatedaqueous sodium bicarbonate solution. The dichloromethane layer wasevaporated and the residue was flash chromatographed on silica gel inhexane:ethyl acetate:methanol (10:10:0.01). The appropriate fractionswere combined and evaporated. The residue was dissolved in anhydrousether and treated with ethereal hydrogen chloride. The precipitate wasfiltered, washed with ether and dried under vacuum to give 1.22 mg(44.8%) of product, mp 165°-170°.

ANALYSIS: Calculated for C₃₁ H₄₉ NO₉.HCl.H₂ O: 58.70% C, 8.28% H, 2.21%N, Found: 58.96% C, 8.02% H, 2.12% N.

EXAMPLE 266β,9α-Dihydroxy-8,13-epoxy-1α-(N-2-propylaminoacetoxy)-7.beta.-(2-tetrahydrofuroyloxy)labd-14-en-11-onehydrochloride hydrate

8,13-Epoxy-7β-(2-tetrahydrofuroyloxy)-1α,6β,9β,9.alpha.-trihydroxylabd-14-en-11-one(400 mg) was combined with N,N-dimethylaniline (117.4 μl) in drydichloromethane (4 ml) at 5° C. under nitrogen. A solution ofbromoacetyl bromide (98.2 μl) in dry dichloromethane (4 ml) was addedand the mixture was stirred at that temperature for 2 hr. The mixturewas allowed to warm to ambient temperature and was quenched withice/water. The mixture was extracted into ethyl acetate and the organicphase washed with dilute aqueous sodium bicarbonate solution, dried overanhydrous sodium sulfate, filtered and evaporated. The residue wasdissolved in dry dichloromethane (2 ml). One ml of the resultant mixturewas added to a solution of 2-propylamine (146.2 μl) in ethyl acetate (1ml). The mixture was stirred under nitrogen at ambient temperatureovernight. The mixture was washed with 1 ml of saturated aqueous sodiumbicarbonate solution, the layers were separated, and the organic phasewas flash chromatographed on silica/gel in hexane:ethyl acetate:methanol(10:10:0.1). The appropriate fractions were combined and evaporated. Theresidue was dissolved in anhydrous ether and treated with etherealhydrogen chloride to provide 100 mg (37.5%) of product, mp 144°-155°.

ANALYSIS: Calculated for C₃₀ H₅₀ ClNO₁₀ : 58.09% C, 8.14% H, 2.26% N,Found: 58.29% C, 8.03% H, 2.25% N.

EXAMPLE 276β,9α-Dihydroxy-8,13-epoxy-1α-(4-morpholinoacetoxy)-7.beta.-(2-tetrahydrofuroyloxy)labd-14-en-11-onehydrochloride hemihydrate

8,13-Epoxy-1α,6β,9α-trihydroxy-7β-(2-tetrahydrofuroyloxy)labd-14-en-11-one(400 mg) was combined with N,N-dimethylaniline (117.4 μl) in drydichloromethane (4 ml) at 5° under nitrogen. A soultin of bromoacetylbromide (98.2 μl) in dry dichloromethane (4 ml) was added and themixture was stirred at 5° for 2 hr. The mixture was allowed to warm toambient temperature, quenched with ice/water, and extracted into ethylacetate. The organic phase was washed with dilute aqueous sodiumbicarbonate solution and dried over anhydrous sodium sulfate, filteredand evaporated. The residue was dissolved in dry dichloromethane (2 ml).One ml of the resultant mixture was added to a solution of morpholine(149.8 μl) in ethyl acetate (1 ml). The mixture was stirred undernitrogen at ambient temperature overnight. The mixture was extractedwith saturated aqueous sodium bicarbonate solution (1 ml). The organicphase was flash chromatographed on silca gel in hexane:ethyl acetate(1:1). The appropriate fractions were combined and evaporated. Theresidue was dissolved in anhydrous ether and treated with etherealhydrogen chloride to provide 110 mg (40.1%) of product, mp 150°-154°.

ANALYSIS: Calculated for C₃₁ H₄₉ ClNO₁₀,5 : 58.24% C, 7.74% H, 2.19% N,Found: 58.54% C, 7.76% H, 2.17% N.

EXAMPLE 288,13-Epoxy-7β-(2-methyltetrahydrofuro-2-yloxy)-1α,6β,9.alpha.-trihydroxy-labd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-tetahydroxylabd-14-en-11-one (500 mg) wascombined with 4-dimethylaminopyridine (174.3 mg),2-methyl-2-tetrahydrofuroic acid (179.2 mg) and dicyclohexylcarbodiimide(308.3 mg) in dichloromethane (50 ml). The mixture was stirred atambient temperature overnight under nitrogen. The mixture was dilutedwith an equal volume of ether, filtered and evaporated. The residue wasflash chromatographed on silica gel in dichloromethane:methanol(10:0.4). The appropriate fractions were combined, evaporated and theresidue was crystallized from cyclohexane:ether to yield 354.6 mg(52.8%) of product, mp 154°-164°.

ANALYSIS: Calculated for C₂₆ H₄₀ O₈ : 64.96% C, 8.41% H, Found: 65.04%C, 8.40% N.

EXAMPLE 291α-(N-t-Butylaminoacetoxy)-6β,9α-dihydroxy-8,13-epoxy-7.beta.-(2-methyltetrahydrofuro-2-yloxy)labd-14-en-11-onehydrochloride hydrate

8,13-Epoxy-1α,6β,9α-trihydroxy-7β-(2-methyltetrahydrofur-2-oyloxy)labd-14-en-11-one(164.0 mg) was dissolved in dichloromethane (2 ml) withN,N-dimethylaniline (44.3 mg) at 0°. A solution of bromoacetyl bromide(83.4 mg) in dichloromethane (2 ml) was added dropwise over 15 min. Themixture was stirred for 2 hr with gradual warming to room temperature.The mixture was partitioned between water and ethyl acetate. The organiclayer was washed with saturated aqueous sodium bicarbonate solution,dried over anhydrous sodium sulfate, filtered and evaporated. Theresidue was dissolved in dichloromethane (1 ml) and stirred with asolution of t-butyl amine (100 mg) in ethyl acetate (2 ml) undernitrogen. The mixture was stirred at ambient temperature overnight,diluted with dichloromethane and washed with saturated aqueous sodiumbicarbonate solution. The organic layer was separated and evaporated.The residue was flash chromatographed on silica gel in hexane:ethylacetate:methanol (10:10:0.1). The appropriate fractions were combinedand evaporated. The residue was dissolved in anhydrous ether and treatedwith ethereal hydrogen chloride to afford 65 mg (29.3%) of product, mp156°-161°.

ANALYSIS: Calculated for C₃₂ H₅₄ ClNIO₁₀ : 59.28% C, 8.41% H, 2.16% N,Found: 59.40% C, 8.41% H, 2.70% N.

EXAMPLE 307β-(2,2-Dimethyl-1,3-dioxolano-4-yloxy)-8,13-epoxy-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd- 14-en-11-one (500 mg) wasdissolved in dichloromethane (50 ml) and stirred with2,2-dimethyl-1,3-dioxolane-4-carboxylic acid potassium salt (250 mg),4-dimethylaminopyridine hydrochloride (215.6 mg) anddicyclohexylcarbodiimide (294.3 mg) overnight, at ambient tempertureunder nitrogen. The mixture was diluted with an equal volume of etherand filtered. The filtrate was evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (3:1). Theappropriate fractions were combined and evaporated to afford 350.8 mg(50.5%) of product, mp 100° (softening).

ANALYSIS: Calculated for C₂₆ H₄₀ O₉ : 62.87% C, 8.13% H, Found: 63.17%C, 8.59% H.

EXAMPLE 317β-(2,3-Dihydroxypropionyloxy)-8,13-epoxy-1α,6β,9α-trihydroxy-labd-14-en-11-one

8,13-Epoxy-7β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one(204 mg) was dissolved in a mixture of 80% acetic acid (2 ml) andmethanol (0.4 ml), under nitrogen, and the mixture was stirred atambient temperature for 3 days. The mixture was evaporated. The residuewas flash chromatographed on silica gel in hexane:ethyl acetate:methanol(10:10:0.01). The appropriate fractions were combined and evaporated.The residue was crystallized from cyclohexane:ether to afford 85.0 mg(45.3%) of product, mp 162°-178°.

ANALYSIS: Calculated for C₂₃ H₃₆ O₉ : 60.50% C, 7.96% H, Found: 60.46%C, 8.05 % H.

EXAMPLE 321α-(N-t-Butylaminoacetoxy)-6β,9α-dihydroxy-7β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-8,11-epoxylabd-14-en-11-onehydrochloride hydrate

7β-(2,2-Dimethyl-1,3-dioxolano-4-yloxy)-8,13-epoxy-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one(500 mg) was dissolved in dry dichloromethane (6 ml) withN,N-dimethylaniline (137.6 μl) under nitrogen. The mixture was cooled to5°. Bromoacetyl bromide (105.6 μl) dissolved in dry dichloromethane (6ml) was added to the stirred solution and the mixture was allowed tostand for 2 hr with gradual warming to ambient temperature. The mixturewas partitioned between ether and water. The organic phase wasseparated, washed with saturate,d aqueous sodium bicarbonate solution,dried over anhydrous sodium sulfate, filtered, and evaporated. Theresidue was dissolved in dichloromethane (5 ml) and stirred undernitrogen with t-butylamine (214.3 ml) dissolved in 10 ml of ethylacetate. The mixture was allowed to stand at ambient temperatureovernight. The mixture was partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate solution. The organic layer wasevaporated. The residue was flash chromatographed on silica gel inhexane:ethyl acetate:methanol (10:10:0.1). The appropriate fractionswere combined and evaporated. The residue was dissolved in ether andtreated with ethereal hydrogen chloride to afford 303.1 mg (45 2%) ofproduct, mp 170°-176° (dec).

ANALYSIS:

Calculated for C₃₂ H₅₄ ClNO₁₁ : 57.85% C, 8.21% H, 2.11% N, Found:58.05% C, 8.02% H, 2.00% N.

EXAMPLE 338,11-Epoxy-7β-(pyroglutamoyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

8,11-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (500 mg) wasdissolved in dichloromethane (50 ml) and stirred together withpyroglutamic acid (175.3 mg), 4-dimethylaminopyridine (174.3 mg) anddicyclohexylcarbodiimide (308.3 mg) overnight at ambient temperature,under nitrogen. The mixture was diluted with an equal volume of etherand filtered. The filtrate was evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate:methanol(10:10:1). The appropriate fraction,s were combined and evaporated. Theresidue was dissolved in ether and precipitated with hexane to afford266.9 mg (41.0%) of product, mp 150°-160°.

ANAYSIS: Calculated for C₂₅ H₃₇ NO₈ : 62.60% C, 7.79% H, 2.92% N, Found:62.94% C, 7.945 H, 2.66% N.

EXAMPLE 348,13-Epoxy-7β-[N-(2-nitrophenylsulfenyl)prolyloxy]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-tetrahydrolabd-14-en-11-one (750 mg) was combinedwith 4-(N,N-dimethylamino)pyridine hydrochloride (323 mg),N-(2-nitrophenylsulfenyl)proline dicyclohexyl ammonium salt (917.2 mg)and dicyclohexylcarbodiimide (505.0 mg) in dichloromethane (50 ml). Themixture was stirred at ambient temperature under nitrogen overnight. Themixture was diluted with an equal volume of ether, filtered andevaporated. The residue was flash chromatographed on silica gel indichloromethane:methanol (10:0.2). The appropriate fractions werecombined and evaporated to dryness. The residue was crystallized fromhexane:ether to afford 880.3 mg of product, mp 125°-129°.

ANALYSIS: Calculated for C₃₁ H₄₂ N₂ O₉ S: 60.17% C, 6.86% H, 4.52% N,Found: 60.69% C, 7.09% H, 4.53% N.

EXAMPLE 35 8,13-Epoxy-1α,6β, 9α-trihydroxy-7β-prolyloxylabd-14-en-11-one

8,13-Epoxy-7β-[N-(2-nitrophenylsulfenyl)prolyloxy)-1α,6β,9α-tribhydroxylabd-14-en-11-one (480 mg) was dissolved in either (20ml). Saturated ethereal hydrogen chloride (2 ml) was added and themixture was stirred for 15 min. The precipitate ws filtered, washed witheither and dried at 80°to yield 125 mg (31.0%) of product, mg 180°-195°.

ANALYSIS: Calculated for C₂₅ H₄₂ ClNO₈ : 57,73% C, 8.16% H, 2.69% N,Found: 58.16% C, 7.89% H, 3.24% N.

EXAMPLE 36 8,13-Epoxy-6-(2-tetrahydrofuroyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-(2-tetrahydrofuroyloxy)-1α,6β,9α-trihydroxylabd-14-en-11one(200 mg) was dissolved in dry tetrahydrofuran (5 ml) and maintained at-78°. Lithium bis(trimethylsilyl)amide (492.2 μl, 1M in tetrahydrofuran)was added and the mixture was warmed to 0°. The mixture was stirred for3 hr after whch additional lithium bis(trimethylsilyl)amide (200 μl, 1Min tetrahydrofuran) was added. After a total time of 6 hr, the reactionwas flash chromatographed on silica gelin hexane:ethyl acetate: methanol(2:1:0.01) to afford 68.0 mg (34.0%) of product, mp 100°-115°.

ANALYSIS: Calculated for C₂₅ H₃₈ O₈ : 64.34% C, 8.23% H, Found: 64.02%C, 8.16% H.

EXAMPLE 371α-(N-t-Butylaminoacetoxy)-7β,9α-dihydroxy-8,13-epoxy-6.beta.-(2-tetrahydrofuroyloxy)labd-14-en-11-one

To a stirred solution of8,13-epoxy-6β-(tetrahydrofurano-2-yloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one(300 mg) in dry dichloromethane (3 ml) containing N,N-dimethylaniline(0.11 ml) in an ice bath, under nitrogen, was added dropwise a solutionof bromoacetyl bromide (0.075 ml) in dichloromethane (6 ml). Thesolution was stirred at 0° for 1 hr. The solution was poured intoice/water/ethyl acetate, extracted with ethyl acetate, washed with coldsodium bicarbonate solution, water and dried over anhydrous sodiumsulfate. Filtration followed by evaporation of solvent provided an oilwhich was dissolved in dichloromethane (3 ml) and added to a solution oft-butylamine (0.3 g) in ethyl acetate (3 ml). The mixture was stirredovernight, poured into ice/water/ethyl acetate. The layers wereseparated and the organic phase was washed twice with water, saturatedsodium chloride solution and dried over anhydrous sodium sulfate.Filtration followed by evaporation of solvent provided an oil. The oilwas dissolved in ether and treated with ethereal hydrogen chloride toprovide 169 mg (41.4%) of product, mp 165°-176°.

ANALYSIS: Calculated for C₃₁ H₄₉ NO₉.HCl.H₂ O: 58.71% C, 8.26% H, 2.21%N, Found: 58 47% C, 8.01% H, 2.13% N.

EXAMPLE 388,13-Epoxy-6β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one(1.4 g) was dissolved in dry tetrahydrofuran (30 ml) under nitrogen andcooled to 5°. Lithium bis(trimethylsilyl)amide (2.82 ml, 1M intetrahydrofuran) was added, with stirring. The mixture was allowed tostand for 2 hr at 5° C. The product was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over anhydrous sodium sulfate, filtered andevaporated. The residue was dissolved in hexane:ethylacetate (3:1) andflash chromatographed on silica gel eluting with 800 ml of hexane:ethylacetate (3:1) followed by 900 ml of hexane:ethyl acetate (2:1). Theappropriate fractions were ccmbined and evaporated. The residue wascrystallized from hexane:ethyl acetate to provide 470 mg (33.6%) ofproduct, mp 110°-120°.

ANALYSIS: Calculated for C₂₆ H₄₀ O₉ : 62.87% C, 8.13% H, Found: 63.25%C, 8.28% H.

EXAMPLE 39 8,13-Epoxy-6β-(2,3-dihydroxypropionyloxy)-1α,7,β,9α-trihydroxy-labd-14-en-11-one

8,13-Epoxy-6β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one(390 mg) was dissolved in 80% acetic acid (4.5 ml) and stirred withmethanol (4.5 ml) at 50° for 2 days, under nitrogen. The solvent wasevaporated and the residue was partitioned between chloroform andsaturated sodium bicarbonate solution. The chloroform extracts werecombined, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was flash chromatographed on silica gel indichloromethane:methanol (19:1). The appropriate. fractions werecombined, evaporated and the residue was dried under vacuum at 100°vernight to afford 91 mg (25.3%) of product, mp 225°-235°.

ANALYSIS: Calculated for C₂₃ H₃₆ O₉ : 60.50% C, 7.96% H, Found: 59.07%C, 7.88% H.

EXAMPLE 40 8,13-Expoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-6,7-carbonate1,9-dimethylformamide acetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one1,9-dimethylformamide acetal (1.059 g) was heated under reflux intoluene (25 ml) containing N,N'-carbonyldiimidazole (0.50 g) andtriethylamine (0.55 ml). After 3 hr, the reaction mixture was evaporatedand the residue was applied directly to a flash chromatograph. Elutionwith 50% ethyl acetate-hexane gave 0.976 g (87%) of product aftercombination of the appropriate fractions. The analytical sample obtainedby recrystallization from hexane had mp 138°-140°.

ANALYSIS: Calculated for C₂₄ H₂₅ NO₇ : 64.12% C, 7.85% H, 3.12% N,Found: 63.91% C, 7.98% H, 3.08% N.

EXAMPLE 418,13-Epoxy-6β-methoxyacetoxy-1α,7β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 0.317 g of8,13-epoxy-7β-methoxyacetoxy-1α,6β,9α-labd-14-en-11-one intetrahydrofuran (75 ml) was added 1M lithium bis(trimethylsilyl)amide inhexanes (1.36 ml) in an ice bath. The solution was stirred 1 hr at 0°,poured into ice/water and extracted with ethyl acetete. The organicextracts were washed three times with water, once with saturated sodiumchloride solution and dried over anhydrous sodium sulfate. Filtrationfollowed by evaporation of solvent provided an oil. The oil wasdissolved in a minimum volume of 35% ethyl acetate/hexane and flashchromatographed on 200 g of silica gel. Evaporation of solvent from theapprcpriate fractions provided 0.147 g (46.4%) of product, mp 164°-165°.

ANALYSIS: Calculated for C₂₃ H₃₆ O₈ : 62.71% C, 8.24% H, Found: 62.58%C, 8.32% H.

EXAMPLE 427β-(1,2:3,4-Diisopropylidine-D-galacturonoyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-trihydroxylabd-14-en-11-one (500 mg),1,2:3,4-diisopropylidine galacturonic acid (410 mg),4-dimethylaminopyridine (180 mg) and dicyclohexylcarbodiimide (35 mg)were dissolved in dichloromethane (50 ml) and stirred under nitrogen atambient temperature overnight. The mixture was filtered and evaporated.The residue was triturated with ethyl acetate and filtered. The filtratewas evaporated and the residue was flash chromatographed on silica gelin dichloromethane:methanol (98:2). The appropriate fractions werecombined and evaporated. The residue was crystallized from hexane:etherto afford 209 mg (24.6%) of product, mp 229°-233°.

ANALYSIS: Calculated for C₃₂ H₄₈ O₁₂ : 61.51% C, 7.76% N, Found: 60.96%C, 7.78% H.

EXAMPLE 437β-[3-(Demethylphosphinyl)propionyloxy]-8,13-epoxy-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

A solution of 8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (600mg), 2-carboxyethyldimethylphosphine oxide (300 mg),dimethylaminopyridine (20 mg), dicyclohexylcarbodiimide (440 mg) anddichloromethane (60 ml) was stirred at room temperature for 16 hrs. Thesuspension was filtered and flash chromatographed (without beingconcentrated) on silica gel (eluent: 4% methanol/dichloromethane).Concentration of the appropriate fractions provided 0.559 g (68.7%) ofproduct, mp 252°-259°.

ANALYSIS: Calculated for C₂₅ H₄₁ O₈ P: 59.98% C, 8.26% H, Found: 59.32%C, 8.81% H.

EXAMPLE 448,13-Epoxy-7β-[2-(methoxyethoxymethoxy)-2-methylpropionyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (0.5 g) in 50 ml ofdry dichloromethane was added 2-hydroxyisobutyric acidmethoxyethoxyethyl ether (0.313 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.313 g)and 4-dimethylaminopyridine (0.166 g). The reaction mixture was stirredat room temperature for 48 hrs, under nitrogen. The mixture was dilutedwith ether, washed three times with water, once with saturated sodiumchloride solution, dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated and the residue was dissolved in a minimumvolume of 20% butyl acetate/hexane and flash chromatographed on silicagel, eluting with 10×200 ml of 20% n-butyl acetate/hexanes, 10×200 ml of25% n-butyl acetate/hexanes, 10×200 ml of 30% n-butyl acetate/hexanes,10×200 ml of 40% n-butyl acetate/hexanes and 10×200 ml of 50% n-butylacetate/hexanes. Concentration of the appropriate fractions provided anoil, which crystallized on standing. Recrystallization fromcyclohexane/ethyl acetate provided 96 mg (10.9%) of product, mp 144°.

EXAMPLE 45 8,13-Epoxy-7β-(2-methoxy-2-methylpropionyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

A solution of 8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (0.5g), dichloromethane (50 ml), 2-methoxy-2-methylpropionic acid (0.175 g),dimethylaminopyridine (0.171 g), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.263 g)was stirred at room temperature for 5 days. The reaction mixture wasdiluted with ether, washed three times with water, once with saturatedsodium chloride solution, dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated. The residue was flashchromatographed on silica gel (eluent: 25% ethyl acetate/hexane). Theappropriate fractions were evaporated. The residue was recrystallizedfrom cyclohexane/ethyl acetate to provide 53 mg (8.4% of product, mp140°-142°.

ANALYSIS: Calculated for C₂₅ H₄₀ O₈ : 64.08% C, 8.60% H, Found: 64.20%C, 8.66% H.

EXAMPLE 468,13-Epoxy-7β-(2-methoxy-2-methylpropionyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one1,9-carbonate

A solution of 8,13-epoxy-1α,6β,7β9α-tetrahydroxylabd-14-en-11-one (2.0g), dicyclohexylcarbodiimide (1.4 g), 2-methoxy-2-methylpropionic acid(0.7 g), 4-dimethylaminopyridine (0.684 g) and dichloromethane (200 ml)was stirred at room temperature overnight. To the suspension was added100 ml of anhydrous ether. The solution was stirred for an additional 10mins and filtered. The filtrate was washed three times with water, oncewith saturated sodium chloride solution and dried over anhydrous sodiumsulfate. The mixture was filtered and the filtrate was evaporated. Theresidue was triturated with ethyl acetate and filtered. The filtrate wasconcentrated to an oil, the residue was dissolved in a minimum volume of25% ethyl acetate/hexane and flash chromatographed on 500 g of silicagel. The appropriate fractions were combined and concentrated. To asolution of the residue in 50 ml of pyridine cooled in an ice-bath,under nitrogen, was added dropwise a solution of 12.5% phosgene intoluene (5 ml). The mixture was stirred for 45 min at ice bathtemperature and 1 hr at room temperature. The mixture was poured intoice water/ethyl acetate, washed three times with water, once withsaturated sodium chloride solution, dried over anhydrous sodium sulfateand filtered. The filtrate was evaporated. The residue was dissolved ina minimum volume of 25% ethyl acetate/hexane and flash chromatographedon 500 g of silica gel. The appropriate fractions were combined andconcentrated. The residue, which crystallized on standing, wasrecrystallized from cyclohexane/ethyl acetate to provide 600 mg (22.3%)of product, mp 135°-138°.

ANALYSIS: Calculated for C₂₆ H₃₈ O₉ : 63.14% C, 7.74% H, Found: 63.04%C, 7.74% H.

EXAMPLE 478,13-Epoxy-7β-(3-furoyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onehemihydrate

8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (500 mg) wascombined with 4-dimethylaminopyridine (174.3 mg), 3-furoic acid (152.2mg) and dicyclohexylcarbodiimide (308.3 mg) in 50 ml of dichloromethaneunder nitrogen. The mixture was stirred overnight at ambienttemperature. The mixture was diluted with an equal volume of ether,filtered, and evaporated to dryness. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (3:1). Theappropriate fractions were combined, evaporated and crystallized fromcyclohexane:ether to afford 232.4 mg (35.2%) of product, mp 241°-244°.

ANALYSIS: Calculated for C₂₅ H₃₅ O₈.5 : 63.67% C, 7.50% H, Found: 63.48%C, 7.27% H.

EXAMPLE 488,13-Epoxy-7β-(2-furoyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (500 mg) wascombined with 174.3 mg of 4-dimethylaminopyridine, 2-furoic acid (152.2mg) and dicyclohexylcarbodiimide (308.3 mg) in 50 ml of dichloromethaneunder nitrogen. The mixture was allowed to stir at ambient temperatureovernight. The mixture was diluted with an equal volume of ether,filtered and evaporated. The residue was flash chromatographed on silicagel in hexane:ethyl acetate (3:1). The appropriate fractions werecombined and evaporated. The residue was crystallized fromcyclohexane:ether to afford 265.3 mg (41.0%) of product, mp 241°-245°.

ANALYSlS Calculated for C₂₅ H₃₄ O₈ : 64.91% C, 7.42% H, Found: 64.88% C,7.25% H.

EXAMPLE 496β-(N-Acetylaminoacetoxy)-8,13-epoxy-1α,7β,9α-trihydroxylabd-14-en-11-one

7β-(N-Acetylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one(630.2 mg) was dissolved in 50 ml of tetrahydrofuran under nitrogen. Thesolution was cooled to 0°, and after 15 min, lithiumbis(trimethylsilyl)amide (2.7 ml of 1M tetrahydrofuran solution) wasadded, followed by stirring for 2 hr at 0°. The reaction mixture wasquenched with 100 ml water, after which the solvent was removed byevaporation. The residue was flash chromatographed on silica gel inhexane:ethyl acetate:methanol (10:10:1). The appropriate fractions werecombined and evaporated. The residue was crystallized from hexane:ethylacetate affording 177.8 mg (28.2%) of product, mp 130°-150°.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₈ : 61.64% C, 7.99% H, 2.99% N,Found: 61.43% C, 7.99% H, 2.82% N.

EXAMPLE 508,13-Epoxy-7β-(2-hydroxy-2-methylpropionyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

A solution of 8,13-epoxy-7β-(2-methoxyethoxymethoxy-2-methylpropionyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one (100 mg) in3:1:1-glacial acetic acid:methanol:water was stirred in a sealed tube at90° for 20 hrs. The reaction mixture was allowed to cool to ambienttemperature, and ether and ice water were added. The solution wasextracted twice with ether, and the ethereal extracts were washed threetimes with water, once with saturated sodium chloride solution, driedover anhydrous sodium sulfate and filtered. The filtrate was evaporated.The residue was dissolved in 30% n-butyl acetate/hexanes and flashedchromatographed on silica gel (100 g), eluting with 30% n-butylacetate/hexanes followed by 40% n-butyl acetate/hexanes. Concentrationof the appropriate fractions provided 12.0 mg. (14.2%) of product as anamorphous solid, mp 155°-177°.

ANALYSIS:

Calculated for C₂₄ H₃₄ O₈ : 63.41% C, 8.43% H, Found: 63.23% C, 8.44% H.##STR15## wherein R₆, R₇, R₁₁, R₁₂, R₁₃, R₁₉, R₂₀ and Z are ashereinbeforedescribed. ##STR16## wherein R₃, R₄, R₅, R₇, R₁₁, R₁₂, R₁₃,and Z are as hereinbeforedescribed. ##STR17## wherein R₆, R₇, R₂₄, R₂₅,R₂₆ and Hal are as hereinbeforedescribed.

We claim:
 1. A process for the preparation of a compound of the formula##STR18## wherein: (a) R₁ is hydrogen;(b) R₆ is a group of the formulaR₈ CO wherein R₈ is hydrogen, loweralkyl, ##STR19## CH₃ CHOH, HOCH₂CHOH, CH₃ C(CH₃)OH, (CH₃)₂ COCH₂ OCH₂ CH₂ OCH₃, CH₃ C(CH₂ OH)₂, C(CH₂OH)₃, ##STR20## wherien R₃₀ is loweralkyl and q is 1, 2 or 3, a group ofthe formula R₁₀ OCR₃₁ R₃₂ (CH₂)_(n) wherein R₁₀ is loweralkyl, R₃₁ ishydrogen or loweralkyl, R₃₂ is hydrogen or loweralkyl, and n is 0, 1, 2or 3; and R₇ is hydrogen; (c) R₉ is hydrogen; and (d) R₁ and R₉ takentogether form a group of the formula CO, a group of the formula SO or agroup of the formula CHNR₁₉ R₂₀ wherein R₁₉ and R₂₀ are eachindependently loweralkyl; and R₁₉ and R₂₀ taken together with thenitrogen atom to which they are attached form a group of the formula##STR21## wherien X is O, S, a group of the formula CHR₁₅ wherein R₁₅ ishydrogen, loweralkyl or a group of the formula OR₁₆ wherein R₁₆ isloweralkyl, and m is 0 or 1; or a group of the formula NR₁₈ wherein R₁₈is loweralkyl, which comprises contacting a compound of the formula##STR22## wherein: (a) R₁ is hydrogen;(b) R₆ is hydrogen; (c) R₇ is agroup of the formula R₈ CO wherein R₈ is as above and n are as above;(d) R₉ is hydrogen; and (e) R₁ and R₉ taken together form a group of theformula CO, a group of the formula SO or a group of the formula CHNR₁₉R₂₀ wherein R₁₉ and R₂₀ are as above; and R₁₉ and R₂₀ taken togetherwith the nitrogen atom to which they are attached form a group of theformula ##STR23## wherein X is O, S, a group of the formula CHR₁₅wherein R₁₅ is as above, a group of the formula OR₁₆ wherein R₁₆ and mis as above, or a group of the formula NR₁₈ wherein R₁₈ is as above inthe presence of an alkali metal bis(triloweralkylsilyl)amide.
 2. Theprocess of claim 1 wherein the alkali metal bis(triloweralkylsilyl)amideis lithium bis(trimethylsilyl)amide.
 3. The process of claim 1 whereinthe reaction is conducted in a solvent.
 4. The process of claim 3wherein the solvent is an ethereal solvent.
 5. The process of claim 4wherein the ethereal solvent is tetrahydrofuran.